Biology subjects

Stanage, T. H.

Publications and source records attributed to Stanage, T. H..

3 recordsLinked to original sources

bioRxiv2025

Distinct ATRX functions cooperate with 9-1-1 and CST complexesto safeguard replication and telomere integrity

Mutations in the ATRX chromatin remodeller predispose to a developmental genetic disorder and cancer, but how it safeguards genome and telomere stability remains unresolved. Here, we uncover critical dependencies for the CTC1-STN1-TEN1 (CST) complex and RAD9A-HUS1-RAD1 (9-1-1) clamp in ATRX deficient cells. ATRX:CST synthetic lethality manifests following accumulation of telomeric G-rich ssDNA, which results in telomere loss and cell death. Conversely, we attribute ATRX:9-1-1 synthetic lethality to genome-wide ssDNA lesions, which compromise DNA replication. We further show ATRX suppresses DNA damage during replication stress by counteracting the activity of the FAM111A protease. We demonstrate that roles of ATRX in telomere maintenance and replication are genetically separable requiring its ATPase activity and PIP-box, respectively, and independently of its DAXX interaction. Collectively, functions of ATRX in suppressing toxic ssDNA lesions are context-dependent and are key to global DNA replication and telomere integrity.

molecular biology↗

bioRxiv2025

SLFN11 restricts escape from telomere crisis to prevent alternative lengthening of telomeres

The tRNA nuclease SLFN11 is epigenetically silenced in [~]50% of treatment-naive tumours and is the strongest predictor of chemoresistance but why it is frequently inactivated in cancer is unknown. To acquire immortality, cancer cells can activate alternative lengthening of telomeres (ALT), typically accompanied by ATRX loss. Here, we implicate SLFN11 in sensing telomere replication stress, triggering eradication of ATRX deficient cells prior to ALT establishment. Whereas progressive telomere shortening of cells lacking telomerase and ATRX leads to telomere crisis and cell death, SLFN11 loss confers tolerance to PML-BLM dependent ALT intermediates, permitting emergence of ALT survivors. We propose that during tumorigenesis SLFN11 inactivation is selected as means to tolerate endogenous replication stress following telomere crisis, leading to the development of therapy resistant tumours before treatment.

molecular biology↗

bioRxiv2021

The Escherichia coli serS gene promoter region overlaps with the rarA gene

Deletion of the entire gene encoding the RarA protein of Escherichia coli results in a growth defect and additional deficiencies that were initially ascribed to a lack of RarA function. Further work revealed that most of the effects reflected the presence of sequences in the rarA gene that affect expression of the downstream gene, serS. The serS gene encodes the seryl aminoacyl-tRNA synthetase. Decreases in the expression of serS can trigger the stringent response. The sequences that affect serS expression are located in the last 15 nucleotides of the rarA gene.

genetics↗